Glaucoma is a family of optic neuropathies that are characterized by irreversible optic nerve damage. It is a serious health problem worldwide. Nearly 67 million people have the disease including >3 million in the United States. It is the 2nd most common cause of irreversible vision loss in the U.S. and the most common cause among African-Americans. It is usually brought on with the onset of age, thus making it a growing problem as the world population ages. The major form of glaucoma in the United States is called primary open angle glaucoma (POAG). Increases in intraocular pressure (IOP) are the major risk factor for POAG. These increases are believed to occur, in most cases, when the movement of aqueous humor through the trabecular meshwork (TM) of the human eye is inhibited. The molecular basis responsible for the impairment in aqueous humor movement is unknown, and it most likely involves multiple causes. One possible factor that may be involved is a disruption in the organization and function of the actin cytoskeleton in the cells found in the TM. Pharmacological agents that disrupt the actin cytoskeleton increase outflow facility in vivo and in vitro and highly crosslinked actin networks are observed in glaucomatous TM cells. Preliminary studies in this laboratory have recently identified a specialized Tiam1/Rac1 signaling pathway that may regulate the activity of the actin cytoskeleton in TM cells. The overall goals of this project are to (1) demonstrate that the Tiam1/Rac1 signaling pathway specifically regulates the organization of the actin cytoskeleton in the TM, (2) determine the best method for targeting this specific Tiam1/Rac1 pathway and (3) determine if targeting the Tiam1/Rac1 pathway can be used to modulate fluid movement through the TM. Studying the mechanisms that regulate the organization and function of the actin cytoskeleton cultures should enhance our understanding of how IOP is controlled. Ultimately, this information will provide important information in the design of new and more specific targets for the treatment of glaucoma which is the long term goal of this project and provide the candidate with a strong background in the molecular and cellular biology skills necessary to conduct translational research in eye disease. [unreadable] [unreadable] [unreadable] [unreadable]